tbuckley/cabot-search huggingface dataset:
Improving Dose-Optimization Processes Used in Oncology Drug Development to Minimize Toxicity and Maximize Benefit to Patients
Authors: Jeanne Fourie Zirkelbach, Mirat Shah, Jonathon Vallejo, Joyce Cheng, Amal Ayyoub, Jiang Liu, Rachel Hudson, Rajeshwari Sridhara, Gwynn Ison, Laleh Amiri-Kordestani, Shenghui Tang, Thomas Gwise, Atiqur Rahman, Richard Pazdur, Marc R. Theoret
Journal: Journal of Clinical Oncology (2022)

This review highlights strategies to integrate dose optimization into premarketing drug development and discusses the underlying statistical principles. Poor dose optimization can have negative consequences for patients, most commonly because of toxicity, including poor quality of life, reduced effectiveness because of inability of patients to stay on current therapy or receive subsequent therapy because of toxicities, and difficulty in developing combination regimens. We reviewed US Food and Drug Administration initial approvals (2019-2021) of small molecules and antibody-drug conjugates for oncologic indications to determine the proportion with a recommended dosage at the maximum tolerated dose or the maximal administered dose, to characterize the use of randomized evaluations of multiple dosages in dose selection, to describe the frequency of dose modifications at the recommended dosage, and to identify case examples that highlight key principles for premarket dose optimization during drug development. Herein, we highlight major principles for dose optimization and review examples of recent US Food and Drug Administration approvals that illustrate how investigation of dose- and exposure-response relationships and use of randomized dose trials can support dose optimization. Although there has been some progress, dose optimization through randomized dose evaluation in oncology trials is not routinely conducted. Dose optimization is essential to ensure that patients receive therapies which maximize efficacy while minimizing toxicity.
Final clinical and pharmacokinetic (PK) results from a phase 1 study of the novel N-cadherin (N-cad) antagonist, Exherin (ADH-1), in patients with refractory solid tumors stratified according to N-cad expression
Authors: D. J. Stewart, D. J. Jonker, R. Goel, G. Goss, J. A. Maroun, C. M. Cripps, J. Wells, W. Wargin, R. K. Malik, W. P. Peters
Journal: Journal of Clinical Oncology (2006)

3016 Background: Malignant transformation and invasiveness correlate with upregulation of N-cad, a cell adhesion molecule expressed on tumor cells and vascular endothelium. N-cad antagonism by ADH-1, a cyclic pentapeptide (CHAVC), causes rapid tumor vascular disruption and apoptosis in preclinical models. We report the final clinical and PK results from the first human study (AHX-01–001). Methods: 46 subjects with incurable solid tumors stratified according to tumor N-cad expression were enrolled. 99 doses of ADH-1 were given by IV bolus or short infusion (31 in a Special Access Program). Doses ranged from 50–1000 mg/m 2 , with 3–6 subjects/cohort. Blood and urine were collected for PK on Day 1, assayed by LC/MS/MS, and a 2 compartment analysis was performed. Results: ADH-1 was generally well tolerated and the maximum tolerated dose was not defined. The most commonly reported adverse events were grade 1–2 fatigue (59%), nausea (32%), dysgeusia (25%), and flushing (20%). 4 subjects in the N-cad positive group (n=28, including 3 N-cad unknown) demonstrated anti-tumor activity; a PR of 6 month duration in refractory esophageal carcinoma; a minor response in lung metastases from an unknown primary following a single dose; and &gt;7 months SD in refractory adrenocortical and colorectal carcinoma. No anti-tumor activity was noted in the N-cad negative group (n=18). The mean initial ADH-1 half-life (t½) was 20 min and the mean terminal phase t½ was 2.2 hr. Mean systemic clearance (CL) was 6.5 L/hr/m 2 . Both t½ and CL were independent of dose. C max increased dose proportionally, ranging from 7 to148 μg/mL, and AUC 0- ∞ tended to increase dose proportionally. The volume of distribution at steady-state (Vss) averaged 14.3 L/m 2 , indicating modest tissue distribution. Approximately 30% of the dose was excreted unchanged in the urine. Conclusions: ADH-1 was generally well tolerated and demonstrated evidence of anti-tumor activity in subjects with N-cad positive tumors. The PK profile was biphasic and the t½ averaged 2.2 hr. C max and AUC 0- ∞ increased dose proportionally, and CL was independent of dose. No significant financial relationships to disclose.
Independent phenotypic plasticity axes define distinct obesity sub-types
Authors: Chih-Hsiang Yang, Luca Fagnocchi, Stefanos Apostle, Vanessa Wegert, Salvador Casaní-Galdón, Kathrin Landgraf, Ilaria Panzeri, Erez Dror, Steffen Heyne, Till Wörpel, Darrell P. Chandler, Di Lu, Tao Yang, Elizabeth Gibbons, Rita Guerreiro, Jose Bras, Martin Thomasen, Louise G. Grunnet, Allan A. Vaag, Linn Gillberg, Elin Grundberg, Ana Conesa, Antje Körner, Timothy Triche, Adelheid Lempradl, Zachary J. DeBruine, Emily Wolfrum, Zachary Madaj, Tim Gruber, Brooke Grimaldi, Andrea Parham, Mitchell J. McDonald, Joseph H. Nadeau, Ildiko Polyak, Carmen Khoo, Christine Lary, Peter D. Gluckman, Neerja Karnani, David Carey, Ruth J. F. Loos, Gabriel Seifert, J. Andrew Pospisilik
Journal: Nature Metabolism (2022)

Studies in genetically 'identical' individuals indicate that as much as 50% of complex trait variation cannot be traced to genetics or to the environment. The mechanisms that generate this 'unexplained' phenotypic variation (UPV) remain largely unknown. Here, we identify neuronatin (NNAT) as a conserved factor that buffers against UPV. We find that Nnat deficiency in isogenic mice triggers the emergence of a bi-stable polyphenism, where littermates emerge into adulthood either 'normal' or 'overgrown'. Mechanistically, this is mediated by an insulin-dependent overgrowth that arises from histone deacetylase (HDAC)-dependent β-cell hyperproliferation. A multi-dimensional analysis of monozygotic twin discordance reveals the existence of two patterns of human UPV, one of which (Type B) phenocopies the NNAT-buffered polyphenism identified in mice. Specifically, Type-B monozygotic co-twins exhibit coordinated increases in fat and lean mass across the body; decreased NNAT expression; increased HDAC-responsive gene signatures; and clinical outcomes linked to insulinemia. Critically, the Type-B UPV signature stratifies both childhood and adult cohorts into four metabolic states, including two phenotypically and molecularly distinct types of obesity.
Most Insured People With Hepatitis C Don’t Get Timely Treatment
Authors: Bridget M. Kuehn
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Annals Graphic Medicine - First Code
Authors: George M. Anderson
Journal: Annals of Internal Medicine (2022)

Web ExclusivesSeptember 2022Annals Graphic Medicine - First CodeFREEGeorge M. Anderson, BSGeorge M. Anderson, BSThe Warren Alpert Medical School of Brown University, Providence, Rhode Island (G.M.A.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G21-0069 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: The Warren Alpert Medical School of Brown University, Providence, Rhode Island (G.M.A.)Disclosures: The author has reported no disclosures of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G21-0069.Author/Illustrator Information: George M. Anderson, BS, is a third-year medical student at the Warren Alpert Medical School of Brown University. More of his artwork can be found at georgemanderson.com (e-mail, [email protected]edu; Twitter, @_georgeanders).This article was published at Annals.org on 13 September 2022. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics September 2022Volume 175, Issue 9Page: W110-W111 ePublished: 13 September 2022 Issue Published: September 2022 Copyright & PermissionsCopyright © 2022 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
The microbiome-derived metabolite TMAO drives immune activation and boosts responses to immune checkpoint blockade in pancreatic cancer
Authors: Gauri Mirji, Alison Worth, Sajad Ahmad Bhat, Mohamed El Sayed, Toshitha Kannan, Aaron R. Goldman, Hsin-Yao Tang, Qin Liu, Noam Auslander, Chi V. Dang, Mohamed Abdel-Mohsen, Andrew Kossenkov, Ben Z. Stanger, Rahul S. Shinde
Journal: Science Immunology (2022)

The composition of the gut microbiome can control innate and adaptive immunity and has emerged as a key regulator of tumor growth, especially in the context of immune checkpoint blockade (ICB) therapy. However, the underlying mechanisms for how the microbiome affects tumor growth remain unclear. Pancreatic ductal adenocarcinoma (PDAC) tends to be refractory to therapy, including ICB. Using a nontargeted, liquid chromatography–tandem mass spectrometry–based metabolomic screen, we identified the gut microbe–derived metabolite trimethylamine N -oxide (TMAO), which enhanced antitumor immunity to PDAC. Delivery of TMAO intraperitoneally or via a dietary choline supplement to orthotopic PDAC-bearing mice reduced tumor growth, associated with an immunostimulatory tumor-associated macrophage (TAM) phenotype, and activated effector T cell response in the tumor microenvironment. Mechanistically, TMAO potentiated the type I interferon (IFN) pathway and conferred antitumor effects in a type I IFN–dependent manner. Delivering TMAO-primed macrophages intravenously produced similar antitumor effects. Combining TMAO with ICB (anti-PD1 and/or anti-Tim3) in a mouse model of PDAC significantly reduced tumor burden and improved survival beyond TMAO or ICB alone. Last, the levels of bacteria containing CutC (an enzyme that generates trimethylamine, the TMAO precursor) correlated with long-term survival in patients with PDAC and improved response to anti-PD1 in patients with melanoma. Together, our study identifies the gut microbial metabolite TMAO as a driver of antitumor immunity and lays the groundwork for potential therapeutic strategies targeting TMAO.
Sensing of SARS-CoV-2 by pDCs and their subsequent production of IFN-I contribute to macrophage-induced cytokine storm during COVID-19
Authors: Paôline Laurent, Chao Yang, André F. Rendeiro, Benjamin E. Nilsson-Payant, Lucia Carrau, Vasuretha Chandar, Yaron Bram, Benjamin R. tenOever, Olivier Elemento, Lionel B. Ivashkiv, Robert E. Schwartz, Franck J. Barrat
Journal: Science Immunology (2022)

Lung-infiltrating macrophages create a marked inflammatory milieu in a subset of patients with COVID-19 by producing a cytokine storm, which correlates with increased lethality. However, these macrophages are largely not infected by SARS-CoV-2, so the mechanism underlying their activation in the lung is unclear. Type I interferons (IFN-I) contribute to protecting the host against SARS-CoV-2 but may also have some deleterious effect, and the source of IFN-I in the lungs of infected patients is not well defined. Plasmacytoid dendritic cells (pDCs), a key cell type involved in antiviral responses, can produce IFN-I in response to SARS-CoV-2. We observed the infiltration of pDCs in the lungs of SARS-CoV-2–infected patients, which correlated with strong IFN-I signaling in lung macrophages. In patients with severe COVID-19, lung macrophages expressed a robust inflammatory signature, which correlated with persistent IFN-I signaling at the single-cell level. Hence, we observed the uncoupling in the kinetics of the infiltration of pDCs in the lungs and the associated IFN-I signature, with the cytokine storm in macrophages. We observed that pDCs were the dominant IFN-α–producing cells in response to the virus in the blood, whereas macrophages produced IFN-α only when in physical contact with infected epithelial cells. We also showed that IFN-α produced by pDCs, after the sensing of SARS-CoV-2 by TLR7, mediated changes in macrophages at both transcriptional and epigenetic levels, which favored their hyperactivation by environmental stimuli. Together, these data indicate that the priming of macrophages can result from the response by pDCs to SARS-CoV-2, leading to macrophage activation in patients with severe COVID-19.
BND-22, a first-in-class humanized ILT2-blocking antibody, promotes antitumor immunity and tumor regression
Authors: Ilana Mandel, Dana Haves Ziv, Ilana Goldshtein, Tsuri Peretz, Dror Alishekevitz, Anna Fridman Dror, Motti Hakim, Sharon Hashmueli, Itay Friedman, Yair Sapir, Rita Greco, Hongjing Qu, Frank Nestle, Dmitri Wiederschain, Lily Pao, Sharad Sharma, Tehila Ben Moshe
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Cancer immunotherapy has revolutionized cancer treatment. However, considering the limited success of immunotherapy to only some cancer types and patient cohorts, there is an unmet need for developing new treatments that will result in higher response rates in patients with cancer. Immunoglobulin-like transcript 2 (ILT2), a LILRB family member, is an inhibitory receptor expressed on a variety of immune cells including T cells, natural killer (NK) cells and different myeloid cells. In the tumor microenvironment, binding of class I MHC (in particular HLA-G) to ILT2 on immune cells mediates a strong inhibitory effect, which manifests in inhibition of antitumor cytotoxicity of T and NK cells, and prevention of phagocytosis of the tumor cells by macrophages. Methods We describe here the development and characteristics of BND-22, a novel, humanized monoclonal antibody that selectively binds to ILT2 and blocks its interaction with classical MHC I and HLA-G. BND-22 was evaluated for its binding and blocking characteristics as well as its ability to increase the antitumor activity of macrophages, T cells and NK cells in various in vitro, ex vivo and in vivo systems. Results Collectively, our data suggest that BND-22 enhances activity of both innate and adaptive immune cells, thus generating robust and comprehensive antitumor immunity. In humanized mice models, blocking ILT2 with BND-22 decreased the growth of human tumors, hindered metastatic spread to the lungs, and prolonged survival of the tumor-bearing mice. In addition, BND-22 improved the antitumor immune response of approved therapies such as anti-PD-1 or anti-EGFR antibodies. Conclusions BND-22 is a first-in-human ILT2 blocking antibody which has demonstrated efficient antitumor activity in various preclinical models as well as a favorable safety profile. Clinical evaluation of BND-22 as a monotherapy or in combination with other therapeutics is under way in patients with cancer. Trial registration number NCT04717375 .
Changing food systems and infectious disease risks in low-income and middle-income countries
Authors: Jeff Waage, Delia Grace, Eric M Fèvre, John McDermott, Jo Lines, Barbara Wieland, Nichola R Naylor, James M Hassell, Kallista Chan
Journal: The Lancet Planetary Health (2022)

The emergence of COVID-19 has drawn the attention of health researchers sharply back to the role that food systems can play in generating human disease burden. But emerging pandemic threats are just one dimension of the complex relationship between agriculture and infectious disease, which is evolving rapidly, particularly in low-income and middle-income countries (LMICs) that are undergoing rapid food system transformation. We examine this changing relationship through four current disease issues. The first is that greater investment in irrigation to improve national food security raises risks of vector-borne disease, which we illustrate with the case of malaria and rice in Africa. The second is that the intensification of livestock production in LMICs brings risks of zoonotic diseases like cysticercosis, which need to be managed as consumer demand grows. The third is that the nutritional benefits of increasing supply of fresh vegetables, fruit, and animal-sourced foods in markets in LMICs pose new food-borne disease risks, which might undermine supply. The fourth issue is that the potential human health risks of antimicrobial resistance from agriculture are intensified by changing livestock production. For each disease issue, we explore how food system transition is creating unintentional infectious disease risks, and what solutions might exist for these problems. We show that successfully addressing all of these challenges requires a coordinated approach between public health and agricultural sectors, recognising the costs and benefits of disease-reducing interventions to both, and seeking win–win solutions that are most likely to attract broad policy support and uptake by food systems.
Hemoperfusion in the intensive care unit
Authors: Zaccaria Ricci, Stefano Romagnoli, Thiago Reis, Rinaldo Bellomo, Claudio Ronco
Journal: Intensive Care Medicine (2022)

Multiple organ failure following a septic event derives from immune dysregulation. Many of the mediators of this process are humoral factors (cytokines), which could theoretically be cleared by direct adsorption through a process called hemoperfusion. Hemoperfusion through devices, which bind specific molecules like endotoxin or theoretically provide non-specific adsorption of pro-inflammatory mediators has been attempted and studied for several decades with variable results. More recently, technological evolution has led to the increasing application of adsorption due to more biocompatible and possibly more efficient biomaterials. As a result, new indications are developing in this field, and novel tools are available for clinical use. This narrative review will describe current knowledge regarding technical concepts, safety, and clinical results of hemoperfusion. Finally, it will focus on the most recent literature regarding adsorption applied in critically ill patients and their indications, including recent randomized controlled trials and future areas of investigation. Clinical trials for the assessment of efficacy of hemoperfusion in septic patients should apply the explanatory approach. This includes a highly selected homogenous patient population. Enrichment criteria such as applying genetic signature and molecular biomarkers allows the identification of subphenotypes of patients. The intervention must be delivered by a multidisciplinary team of trained personnel. The aim is to maximize the signals for efficacy and safety. In a homogenous cohort, confounding uncontrolled variables are less likely to exist. Trials with highly selected populations have a high internal validity but poor generalizability. The parallel design described in the figure is robust and usually is required by regulatory agencies for the approval of a new treatment. Allocation concealment and randomization are key to minimize bias such as confirmation bias, observer bias. The intervention should be delivered following a strict protocol. Deviations from the protocol might negatively influence the potential effects of the therapies. Surrogates such as cytokine measurement are adequate primary outcomes in phase 3 trials with small sample size because there is a higher likelihood of finding positive results concerning surrogate markers than in respect with clinical outcomes. Once a trial shows positive results concerning surrogate markers, a rationale for another phase 3 trial exploring clinical outcomes is built, justifying the allocation of financial sources to the intended trial.
Dynamic gelatin-based hydrogels promote the proliferation and self-renewal of embryonic stem cells in long-term 3D culture
Authors: xiayi xu, Qian Feng, Xun Ma, Yingrui Deng, Kunyu Zhang, Hon Son Ooi, Boguang Yang, Zhi-Yong Zhang, Bo Feng, Liming Bian
Journal: Biomaterials (2022)
TCT-260 Comparison of the SYNTAX Score 2020 Based on Coronary Artery Computed Tomography (CCTA) or Invasive Coronary Angiography (ICA)
Authors: Patrick Serruys, Shinichiro Masuda, Shigetaka Kageyama, Nozomi Kotoku, Kai Ninomiya, Ulrich Schneider, Torsten Doenst, Yoshinobu Onuma
Journal: Journal of the American College of Cardiology (2022)
TCT-264 Prognostic Value of Coronary Flow Capacity Derived From [15O]H2O Positron Emission Tomography Perfusion Imaging
Authors: Ruben de Winter, Ruurt Jukema, Pepijn van Diemen, Stefan Schumacher, Yvemarie Somsen, Tim Van de Hoef, Albert van Rossum, Jos Twisk, Teemu Maaniitty, Juhani Knuuti, Antti Saraste, Alexander Nap, Pieter Raijmakers, Ibrahim Danad, Paul Knaapen
Journal: Journal of the American College of Cardiology (2022)
TCT-267 Comparison Between Functional and Angiographical Approaches Guiding Percutaneous Coronary Intervention: A Network Meta-Analysis of Randomized Controlled Trials
Authors: Yoshikazu Kishino, Hiroki Ueyama, Tatsunori Takahashi, Yuhei Kobayashi, Hisato Takagi, Toshiki Kuno
Journal: Journal of the American College of Cardiology (2022)
TCT-270 Impact of Eruptive- Versus Nodular-Calcified Nodule Morphology on Acute and Long-Term Outcomes After Stenting
Authors: Takao Sato, Mitsuaki Matsumura, Kei Yamamoto, Jeffrey Moses, Susan Thomas, David Cohen, Gary Mintz, Richard Shlofmitz, Ziad Ali, Akiko Maehara
Journal: Journal of the American College of Cardiology (2022)
TCT-271 Incidence and Predictors of Longitudinal Stent Elongation: Insights From Pooled Analysis of Indian Single Centre Drug-Eluting Stent Cohort
Authors: Ganesan Nambirajan, Sampath Kumar, R. Sivakumar, Selvamani Sethuraman, Jayapandian Pandian, Thomasxavier Paulsingh, Arun Kumar Kannan
Journal: Journal of the American College of Cardiology (2022)
TCT-269 FFR-Guided Versus Angiography-Guided PCI in Multivessel Coronary Artery Disease: A Meta-Analysis of RCTs
Authors: Connor Matthews, Kate Naylor, John Greenwood, Abdul Mozid, Jennifer Rossington, Murugapathy Veerasamy, Heerajnarain Bulluck
Journal: Journal of the American College of Cardiology (2022)
TCT-262 Screening Selection According to the SYNTAX Score 2020 in the FASTTRACK CABG—A First in Man Study—Assessing the Feasibility and Safety of Sole MSCT Guidance for CABG Performance
Authors: Patrick Serruys, Shinichiro Masuda, Shigetaka Kageyama, Nozomi Kotoku, Marie-Angele Morel, Jonathon Leipsic, Ulrich Schneider, Torsten Doenst, Yoshinobu Onuma, Kai Ninomiya
Journal: Journal of the American College of Cardiology (2022)
TCT-268 Comparison of Fractional Flow Reserve vs Intravascular Ultrasound Guided Percutaneous Coronary Intervention in the Treatment of Long Coronary Artery Lesions: One Year Invasive Follow-Up
Authors: Povilas Budrys, Arvydas Baranauskas, Giedrius Davidavicius
Journal: Journal of the American College of Cardiology (2022)
TCT-263 Viability and Ischemia Assessment in Chronic Coronary Total Occlusions According to Collaterals Distribution: A Stress CMR Study
Authors: Giuseppe Pinto, Mauro Chiarito, Gaetano Liccardo, Sara Baggio, Fabio Fazzari, Federica Catapano, Gabriele Gasparini, Giulio Stefanini, Lorenzo Monti
Journal: Journal of the American College of Cardiology (2022)